Osteoarthritis is one of the major causes of disability, yet its pathogenesis still remains to be defined in sufficient detail to permit a rational approach to arresting its progress or to the prevention of its development. since it is primarily a disease of later life, some aspect of the aging process must set the stage for its development. This proposal marshals the expertise of individuals from a wide range of disciplines, ranging from chemistry, biochemistry and molecular genetics to clinical medicine, and orthopedic surgery to focus their skills on age-related changes in structural biology, chemical composition, metabolic activity, humoral response and genetic expression of both rabbit and human joint structures and the effect of various stages of osteoarthritis on these measurements. The progressive increase of frequency of both chondrocalcinosis and of osteoarthritis with advancing age, further strengthens the reason and importance of delineation of the underlying metabolic basis of a high pyrophosphate content of cartilage cells, fibroblasts and lymphoblasts cultured from patients affected with chondrocalcinosis, an observation first made at UCSD. As a result of the progress made over two years of interaction of the major members of this ongoing Program Project Grant, new concepts have been formed. Starting with the clinical observations of a six-fold increase in concurrence of osteoarthritis and chondrocalcinosis and the reverse situation, a lack of concurrence between osteoporosis and osteoarthritis, a new working hypothesis for relating these observations at a biochemical level has been developed that is to be tested. The possible role of a more dense subchondral bone being a factor inducing increased stresses on cartilage will be correlated with biochemical changes of their cells. The possible role of aging and disuse induced laxity in major tendons of the joint capsule will be evaluated in rabbits. Rabbits are also being used to generate osteoarthritis by the Hulth method. The possible role of age- induced biochemical alterations in Matrix components of cartilage and bone will be evaluated. It also holds the potential for providing a new insight into mechanism for regulating some of these biochemical features, such as intracellular pyrophosphate which holds promise of possible new avenues for improving the early diagnosis, treatment and possible prevention of osteoarthritis and associated diseases.